Current stem cell-based strategies for tissue regeneration involve ex vivo manipulation of these cells to confer features of the desired progenitor population. Despite being a valid approach, cell transplantation has encountered crucial barriers in therapeutic translation, including immune rejection; pathogen transmission; potential tumorigenesis; issues associated with packaging, storage, and shipping; and difficulties in clinical adoption and regulatory approval.
Perivascular tendon stem/progenitor cells (PTSCs) are a small population of multipotent cells that play a critical role in tendon healing and regeneration. While connective tissue growth factor (CTGF) has been shown to induce PTSCs to differentiate into tendon cells and helps to recruit PTSCs to the site of injury following tendon rupture, the clinical use of CTGF as a therapy for tendon injury may be limited by the many challenges typically associated with biologics.
CTGF is known to recruit CD146+ perivascular tendon stem/progenitor cells (PTSCs) to the site of injury following tendon rupture; induce differentiation of PTSCs into tendon cells; and regenerate fully transected tendons (Lee, et al., J. Clin. Invest. 125:2690-2701, 2015). CTGF-induced proliferation and tenogenic differentiation of PTSCs are regulated by the focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) ½ pathway (Lee, et al., 2015, supra), consequently leading to tendon regeneration in rats.
CTGF can selectively enrich PTSCs in the early phase of tendon healing and induce tenogenic differentiation in the later phase (Lee, et al., 2015, supra). Localized delivery of CTGF can promote healing and regeneration of transected tendons in vivo by inducing a transient increase in PTSCs (Lee, et al., 2015, supra).
The PTSCs are a small population of multipotent cells that play a critical role in tendon healing and regeneration, and the stimulation of tenogenic differentiation of PTSCs is a key to regenerate torn tendons (see, e.g., Lee, et al., 2015, supra). PTSCs can be found in the perivascular niche and express both tendon- and stem cell-like characteristics (Tempfer, et al., Histochem. Cell Biol. 131:733-741, 2009; Lee, et al., 2015, supra).
Despite these promising results, however, the clinical use of CTGF as a therapy for tendon injury may be limited by the many challenges typically associated with biologics, which include high cost, immunogenicity, and the necessity for complex delivery systems.
Oxotremorine M (Oxo-M) and PPBP maleate (4-PPBP) are receptor agonists which activate the same signaling pathway that regulates CTGF-mediated tenogenic differentiation of PTSCs. Oxo-M has been identified as a muscarinic receptor agonist that can elicit FAK signaling in neuronal cells (Linseman, et al., J. Neurochem. 73:1933-1944, 1999). 4-phenyl-1-(4-phenylbutyl) piperidine (4-PPBP) is a small molecule σ1 receptor agonist that can elicit ERK1/2 phosphorylation in primary neurons (Tan, et al., Neuropharmacology 59:416-424, 2010).